Overall DNA methylation and chromatin structure of normal and abnormal X chromosomes

Abstract

DNA methylation patterns were studied at the chromosome level in normal and abnormal X chromosomes using an anti-5-methylcytosine antibody. In man, except for the late-replicating X of female cells, the labeled chromosome structures correspond to R- and T-bands and heterochromatin. Depending on the cell type, the species, and cell culture conditions, the late-replicating X in female cells appears to be more or less undermethylated. Under normal conditions, the only structures that remain methylated on the X chromosomes correspond to pseudoautosomal regions, which harbor active genes. Thus, active genes are usually hypomethylated but are located in methylated chromatin. Structural rearrangements of the X chromosome, such as t(X;X)(pter;pter), induce a Turner syndrome-like phenotype that is inconsistent with the resulting triple-X constitution. This suggests a position effect controlling gene inactivation. The derivative chromosomes are always late replicating, and their duplicated short arms, which harbor pseudoautosomal regions, replicate later than the normal late-replicating X chromosomes. The compaction or condensation of this segment is unusual, with a halo of chromatin surrounding a hypocondensed chromosome core. The chromosome core is hypomethylated, but the surrounding chromatin is slightly labeled. Thus, unusual DNA methylation and chromatin condensation are associated with the observed position effect. This strengthens the hypothesis that DNA methylation at the chromosome level is associated with both chromatin structure and gene expression.

Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome

“…This observation is consistent with a number of reports that have indicated that the overall levels of methylation on Xi are reduced relative to Xa and autosomes (Bernardino-Sgherri et al., 2002; Bernardino et al., 2000; Hellman and Chess, 2007; Viegas-Pequignot et al., 1988; Weber et al., 2005), and moreover that Xi is hypomethylated at intronic CpGs (Hellman and Chess, 2007; Lock et al., 1986). …”

Late-replicating heterochromatin is characterized by decreased cytosine methylation in the human genome

“…However, there is reason to question the association of cytosine methylation with facultative heterochromatin formation, as it has been recognized for some time that the inactive X chromosome in females is globally hypomethylated (Bernardino-Sgherri et al 2002), possibly related to the decreased methylation in bodies of genes (Hellman and Chess 2007) silenced as part of the X inactivation process.…”

Short stature and primary ovarian insufficiency possibly due to chromosomal position effect in a balanced X;1 translocation

“…5 ). This situation might lead to functional mosaic aneusomy of some translocated genes and/or gene regulators in this region [ 32 , 33 ].

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